Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

Ilaria Cervellini,Manuela Mengozzi,Thomas Brenton,Pietro Ghezzi,Alexander Annenkov,Yuti Chernajovsky

doi:10.2119/molmed.2013.00013

Abstract

Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in nonhematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein [MOG] and myelin basic protein [MBP]). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by Western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects.

Highlights

Erythropoietin (EPO) has protective effects and decreases neuroinflammation in various models of neurological diseases, including traumatic and ischemic injury of the brain and the spinal cord and multiple sclerosis (MS) [1,2]
We investigated the role of early growth response gene 2 (Egr2), a gene required for myelination in the peripheral nervous system [27], whose expression is induced by EPO in the brain [6]
This study shows that EPO increases the expression of myelin genes (MOG and myelin basic protein (MBP)) in differentiated CG4-EPO receptor (EPOR) cells, and that this effect requires EPOR

Summary

Introduction

Erythropoietin (EPO) has protective effects and decreases neuroinflammation in various models of neurological diseases, including traumatic and ischemic injury of the brain and the spinal cord and multiple sclerosis (MS) [1,2]. In the context of MS, EPO has antiinflammatory [7,8] and immunoregulatory properties [9,10]. It inhibits demyelination and axonal damage [11,12], but it is unclear whether this effect is secondary to its antiinflammatory and immunoregulatory action. There are evidences that EPO is effective in nonimmune models of demyelination. EPO is protective in vivo in a model of chemically induced demyelination [13] and induces myelin repair in an ex vivo model of demyelination induced by lysolecithin [14]. EPO increases the number of myelin basic protein (MBP)-positive cells in primary oligodendrocytes [15]

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Discussion

Conclusion